Attention deficit disorder (ADD) is a learning disorder which relates to developmentally inappropriate inattention and impulsivity which may be present with or without hyperactivity. Attention deficit disorder is implicated in learning disorders and can influence the behavior of children at any cognitive level. ADD is primarily a disorder experienced by children, but it may be present in adults as well. ADD is estimated to affect 5 to 10% of school-aged children, precipitating half of the childhood referrals to diagnostic clinics and it is seen 10 times more frequently in boys than girls. A common disorder, ADD probably accounts for more child mental health referrals than any other single disorder. Attention deficit disorder may also be referred to as disruptive behavior disorder.
The primary signs of attention deficit disorder with or without hyperactivity are a subject's display of inattention and impulsivity. Attention deficit disorder with hyperactivity is diagnosed when the signs of overactivity are obvious. Inappropriate inattention causes increased rates of activity and impersistence or reluctance to participate or respond. A subject suffering from ADD exhibits a consistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. Such subjects must suffer clear evidence of interference with developmentally appropriate social, academic, or occupational functioning. Although subjects with ADD and without hyperactivity may not manifest high activity levels, most exhibit restlessness or jitteriness, short attention span, and poor impulse control. These are qualitatively different from those seen in conduct and anxiety disorders. Inattention is described as a failure to finish tasks started, easy distractibility, seeming lack of attention, and difficulty concentrating on tasks requiring sustained attention. Impulsivity is described as acting before thinking, difficulty taking turns, problems organizing work, and constant shifting from one activity to another. Impulsive responses are especially likely when involved with uncertainty and the need to attend carefully. Hyperactivity is featured as difficulty staying seated and sitting still, and running or climbing excessively.
DSM-III-R lists 14 signs, 8 of which must be present for the diagnosis of attention deficit disorder. These are (1) often fidgets with hands or feet or squirms in seat (restlessness), (2) has difficulty remaining seated when required to do so, (3) is easily distracted by extraneous stimuli, (4) has difficulty awaiting turn in games or group situations, (5) often blurts out answers before questions are completed, (6) has difficulty following through on instructions from others (not due to oppositional behavior or failure of comprehension), (7) has difficulty sustaining attention in tasks or play activities, (8) often shifts from one uncompleted task to another, (9) has difficulty playing quietly, (10) often talks excessively, (11) often interrupts or intrudes on others, (12) often does not seem to listen to what is being said, (13) often loses things necessary for tasks or activities at school or home, and (14) often engages in physically dangerous activities without considering possible consequences. As used herein, the term attention deficit disorder shall include disruptive behavior disorder as characterized in DSM-IV-R (Diagnostic and Statistical Manual of Mental Disorders, Revised) as categories 314.xx (including 314.01, 314.00 and 314.9), 312.xx and 313.xx. The skilled artisan will recognize that there are alternate nomneclatures, nosologies, and classification systems for pathological conditions and that these systems evolve with medical scientific progress.
Primary signs tend to appear when the attention deficit disorder patient is involved in vigilance and reaction-time tasks and tasks requiring visual and perceptual search, paired associate learning, systematic listening, continuous performance, and directed attention. Inattention and impulsivity restrict development of academic skills and concepts, thinking and reasoning strategies, motivation for school, and adjustment to social demands. Behavior of patients suffering from attention deficit disorder often is more resistant to treatment than that of patients with other behavioral disorders. Associated or secondary signs are frequently noted: motor incoordination, nonlocalized "soft" neurologic findings, perceptual-motor dysfunctions, EEG abnormalities, emotional lability, opposition, anxiety, aggressiveness, low frustration tolerance, and poor peer relationships.
Onset of attention deficit disorder occurs typically before age 4 yr and invariably before age 7 yr. The peak age for referral has been between 8 and 10 yr. Early indicators vary, but most children diagnosed as having ADD with or without hyperactivity at school age exhibited delays in motor development, tended to have brief attention spans (eg, did not play with toys or did so in brief intervals), and usually had higher activity levels than normal during their preschool years. Children with hyperactivity often were described as hyperexcitable and were difficult to manage as toddlers and preschoolers. In school these signs persist, and difficulty with visual motor tasks such as copying and printing may become apparent. Right-left confusion and immature coordination after age 7 yr are prevalent in both types of ADD. Some children with ADD signs also have been less responsive to positive and negative reinforcement. They often seem to lack intrinsic motivation and do not consider long-term consequences of their behavior. In general, children with ADD during the school years are a more homogeneous group than those referred before age 6 yr. Many ADD signs expressed during the preschool years indicate communication disorders, anxiety, and conduct disorders. During later childhood, ADD signs usually are specific and qualitatively distinct; eg, such children often exhibit continuous movement of the lower extremities, motor impersistence such as the purposeless movement and fidgeting of hands, impulsive talking, and a seeming lack of awareness of their environment. Commonly, they are not aggressive or oppositional. Some studies have found that about 20% have learning disabilities, 40% exhibit depressed behavior by adolescence, 60% have problems such as aggressiveness, temper tantrums, and low frustration tolerance with little provocation, and 90% have academic problems.
Adolescents and adults may display residual symptoms of inattention and impulsivity such as fidgetiness, restlessness, difficulty completing assigned tasks (eg, homework), difficulty focusing attention for extended periods of time and difficulty engaging in quiet sedentary activities. Although hyperactivity tends to diminish with age, residual symptoms and signs can extend well into adulthood. Follow-up studies have found that children identified as having ADD do not grow out of their difficulties. Later problems in adolescence and adulthood occur predominantly as academic failure, low self-esteem, and difficulty learning appropriate social behavior. Some studies have found that adolescents and adults with histories of ADD with impulsivity have a high incidence of personality trait disorders and antisocial behavior; most continue to display impulsivity, restlessness, and poor social skills. ADD individuals with hyperactivity seem to adjust better in work than in academic situations. Interpersonal and social problems often persist into adulthood; suicide attempts (not related to methylphenidate) have been reported as higher when compared with those in the normal population. Low intelligence, aggressiveness, social and interpersonal problems, and parental psychopathology are predictors of poor outcomes in adulthood.
No single treatment has been completely effective for attention deficit disorder. Psychostimulant medications combined with behavioral and cognitive therapies (eg, self-recording, self-monitoring, modeling, and role-playing) have the greatest controlling influence on symptom expression. Used alone, medication has been effective predominantly with less aggressive ADD children coming from stable home environments. Elimination diets, megavitamin treatments, psychotherapy, and biochemical interventions (eg, the administration of neurochemicals) have had only minor, unsustained effects.
Methylphenidate (RITALIN.RTM.) is the drug of choice for the treatment of prevention of ADD. Methylphenidate is generally more effective than tricyclic antidepressants (eg, imipramine), caffeine, and other psychostimulants (eg, pemoline and deanol) and has fewer side effects than does dextroamphetamine. A preferred form in development is d-methylphenidate hydrochloride. Common side effects of methylphenidate are sleep disturbances (eg, insomnia), depression or sadness, headache, stomachache, suppression of appetite, elevated BP, and, with large continuous doses, a reduction of growth. Long-term benefits of medication with methylphenidate, however, have not been demonstrated conclusively. Some research indicates that use of medication permits participation in activities previously inaccessible because of poor attention and impulsivity. These approaches have had limited success, however, and an alternate means of treating or preventing attention deficit disorders would be of great benefit.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42, 1295-1305 (1988)).
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3, respectively.
Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). Substance P is an excitatory neurotransmitter which stimulates the activity of dopamine and perhaps other neurotransmitters thought to be involved in movement and attention. In accordance with the present invention, a neurokinin-1 receptor antagonist should be effective in directly reducing hyperactive states and in focusing the attention of a patient with attention deficit disorder.
Neurokinin-1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, PCT Patent Publication Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, PCT Patent Publication No. WO 96/24353 suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI. Currently there are only limited means for treating attention deficit disorder. In view of the short-comings of existing agents, there is a need for new effective methods for treating or preventing attention deficit disorder.